儿童癌症中易感基因的种系突变
Germline Mutations in Predisposition Genes in Pediatric Cancer.
作者信息
Zhang Jinghui, Walsh Michael F, Wu Gang, Edmonson Michael N, Gruber Tanja A, Easton John, Hedges Dale, Ma Xiaotu, Zhou Xin, Yergeau Donald A, Wilkinson Mark R, Vadodaria Bhavin, Chen Xiang, McGee Rose B, Hines-Dowell Stacy, Nuccio Regina, Quinn Emily, Shurtleff Sheila A, Rusch Michael, Patel Aman, Becksfort Jared B, Wang Shuoguo, Weaver Meaghann S, Ding Li, Mardis Elaine R, Wilson Richard K, Gajjar Amar, Ellison David W, Pappo Alberto S, Pui Ching-Hon, Nichols Kim E, Downing James R
机构信息
Departments of Computational Biology (J.Z., G.W., M.N.E., D.H., X.M., X.Z., M.R.W., X.C., M.R., A.P., J.B.B., S.W.), Oncology (M.F.W., T.A.G., R.B.M., S.H.-D., R.N., E.Q., A.G., A.S.P., C.-H.P., K.E.N.), and Pathology (T.A.G., M.R.W., S.A.S., D.W.E., C.-H.P., J.R.D.) and the Pediatric Cancer Genome Project (J.Z., M.F.W., G.W., M.N.E., T.A.G., J.E., X.M., D.A.Y., B.V., X.C., R.B.M., S.H.-D., R.N., E.Q., S.A.S., M.R., A.P., J.B.B., S.W., M.S.W., A.G., D.W.E., A.S.P., C.-H.P., K.E.N., J.R.D.), St. Jude Children's Research Hospital, Memphis, TN; and the Department of Genetics and McDonnell Genome Institute, Washington University School of Medicine in St. Louis, St. Louis (L.D., E.R.M., R.K.W.).
出版信息
N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.
BACKGROUND
The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.
METHODS
In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).
RESULTS
Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.
CONCLUSIONS
Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).
背景
癌症患儿和青少年中易感性突变的患病率和谱系很大程度上尚不清楚。了解此类突变可能有助于增进对肿瘤发生的理解、指导患者护理，并为患者及其家庭提供遗传咨询。
方法
在1120名20岁以下的患者中，我们对595名患者进行了全基因组测序，对456名患者进行了全外显子组测序，69名患者同时进行了这两种测序。我们分析了565个基因的DNA序列，包括60个与常染色体显性癌症易感性综合征相关的基因，以寻找种系突变。由一组医学专家利用癌症特异性和位点特异性遗传数据库、医学文献、计算预测以及在肿瘤基因组中发现的二次打击来确定突变的致病性。采用相同的方法分析了千人基因组计划中966名无已知癌症者的数据，并采用类似方法分析了一项自闭症研究的数据（来自515名自闭症患者和208名非自闭症患者）。
结果
在95名癌症患者（8.5%）中发现了被认为是致病性或可能致病性的突变，而在千人基因组计划中的人群中这一比例为1.1%，在自闭症研究的参与者中为0.6%。受影响患者中最常发生突变的基因是TP53（50名患者）、APC（6名）、BRCA2（6名）、NF1（4名）、PMS2（4名）、RB1（3名）和RUNX1（3名）。另有18名患者在肿瘤抑制基因中存在蛋白质截短突变。在58名有易感性突变且有家族史信息的患者中，23名（40%）有癌症家族史。
结论
在8.5%的癌症患儿和青少年中发现了癌症易感基因的种系突变。在大多数患者中，家族史并不能预测潜在的易感性综合征的存在。（由美国黎巴嫩叙利亚联合慈善机构和美国国立癌症研究所资助。）
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